JP6598381B2 - Corneal thickness regulator - Google Patents
Corneal thickness regulator Download PDFInfo
- Publication number
- JP6598381B2 JP6598381B2 JP2016550333A JP2016550333A JP6598381B2 JP 6598381 B2 JP6598381 B2 JP 6598381B2 JP 2016550333 A JP2016550333 A JP 2016550333A JP 2016550333 A JP2016550333 A JP 2016550333A JP 6598381 B2 JP6598381 B2 JP 6598381B2
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- corneal
- cornea
- thickness
- compound
- homopiperazine
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Description
本発明は、角膜厚調節剤に関する。より詳細には、本発明は、１−（４−フルオロ−５−イソキノリンスルホニル）−２−メチル−１，４−ホモピペラジン若しくはその塩又はそれらの溶媒和物を有効成分として含有してなる角膜厚調節剤に関する。 The present invention relates to a corneal thickness regulator. More specifically, the present invention relates to a cornea comprising 1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof as an active ingredient. It relates to a thickness regulator.
角膜は、強膜と共に眼球壁を構成する重要な組織であると同時に、透明組織として外界の像を眼内に取り入れる入口でもある。角膜は、他の生体組織とは異なり無血管で透明であり、両面が滑らかな球面となっている。角膜の外側の表面は涙液層で覆われ、内側は房水で満たされた前房に接している。
角膜の厚さは中央部で約５００μｍであり、外側から角膜上皮、ボーマン膜（Bowman membrane）、実質、デスメ膜（Descemet membrane）、及び内皮の５層からなっている。角膜上皮層は角膜全体の厚さの約１０％であり、角膜上皮細胞で形成されている。角膜上皮に損傷が生じた場合には、周辺の上皮細胞が移動し、増殖して損傷部分を修復する。角膜実質は角膜全体の厚さの約９０％を占めている。角膜実質の主成分はコラーゲンであるが、他にムコ多糖を含んでいる。このムコ多糖は吸水性で、常に水分を吸収してふくれよう（膨潤）としている。しかし、角膜内皮のポンプ機能及びバリア機能により、角膜実質の含水率は常に一定に保たれている。The cornea is an important tissue that constitutes the eyeball wall together with the sclera, and at the same time, is an entrance for taking an image of the outside world as a transparent tissue into the eye. Unlike other biological tissues, the cornea is avascular and transparent, and has a smooth spherical surface on both sides. The outer surface of the cornea is covered with a tear film and the inner side is in contact with the anterior chamber filled with aqueous humor.
The thickness of the cornea is about 500 μm at the center, and is composed of five layers of corneal epithelium, Bowman membrane, parenchyma, Descemet membrane, and endothelium from the outside. The corneal epithelial layer is about 10% of the total thickness of the cornea and is formed of corneal epithelial cells. When the corneal epithelium is damaged, the surrounding epithelial cells move and proliferate to repair the damaged part. The corneal stroma accounts for about 90% of the total thickness of the cornea. The main component of the corneal stroma is collagen, but it also contains mucopolysaccharide. This mucopolysaccharide is water-absorbing and always absorbs moisture and swells (swells). However, the water content of the corneal stroma is always kept constant by the pump function and the barrier function of the corneal endothelium.
角膜内皮は、角膜内皮細胞でできており、ヒトの角膜内皮細胞は細胞***しないので、一度脱落すると再生しない。ヒトの角膜内皮細胞が損傷を受け脱落して欠損すると、増殖により修復することはできず、周囲の内皮細胞が移動し、伸展して新たな細胞接着を形成して欠損部を補うことになる。このため、ヒトの角膜内皮細胞の接着性は損傷部位の修復のための重要な機能となる。また、損傷が甚大となると、限りある細胞数での修復が不可能となり、角膜内皮に欠損部位ができることになる。角膜内皮に欠損部位ができると、不可逆性の重篤な機能不全となる。具体的には、角膜内皮細胞の密度が約５００個／ｍｍ２以下になると、角膜内皮の欠損部位を修復することができなくなり、角膜に浮腫が生じ（水疱性角膜症）、不可逆性の混濁となる。なお、正常な角膜内皮細胞の密度は約２５００〜３０００個／ｍｍ２であるとされている。
角膜内皮細胞は、水を吸収して膨潤しようとする角膜実質から水を前房に排出するポンプ機能、及び前房から角膜実質への水の移動を制御するバリア機能を有している。角膜内皮細胞のこれらの機能が低下すると、角膜実質が過剰の水分を含むことになり、角膜の厚みが増すだけでなく、浮腫が生じ（水疱性角膜症）、不可逆性の混濁となり、視力が極度に低下することになる。角膜の膨潤は角膜の厚さを増加させ、浮腫の発生を惹起させるに至ることから、角膜を菲薄化し角膜の膨潤を防止する必要がある。The corneal endothelium is made up of corneal endothelial cells, and human corneal endothelial cells do not divide and therefore do not regenerate once they fall off. When human corneal endothelial cells are damaged and dropped and lost, they cannot be repaired by proliferation, and the surrounding endothelial cells migrate and stretch to form new cell adhesions to make up for the defect. . For this reason, the adhesion of human corneal endothelial cells is an important function for repairing damaged sites. In addition, if the damage becomes enormous, repair with a limited number of cells becomes impossible, and a defective site is formed in the corneal endothelium. When a defect site is formed in the corneal endothelium, irreversible serious dysfunction is caused. Specifically, when the density of corneal endothelial cells is about 500 cells / mm 2 or less, it becomes impossible to repair the defective portion of the corneal endothelium, edema occurs in the cornea (bullous keratopathy), and irreversible turbidity It becomes. Note that the density of normal corneal endothelial cells is about 2500 to 3000 cells / mm 2 .
The corneal endothelial cells have a pump function that discharges water from the corneal stroma to absorb and swell water to the anterior chamber, and a barrier function that controls movement of water from the anterior chamber to the corneal stroma. When these functions of corneal endothelial cells are reduced, the corneal stroma contains excess water, which not only increases the thickness of the cornea, but also causes edema (bullous keratopathy), irreversible turbidity, and visual acuity It will fall extremely. Since the swelling of the cornea increases the thickness of the cornea and causes the occurrence of edema, it is necessary to thin the cornea and prevent the cornea from swelling.
角膜内皮の機能不全は、角膜の機能不全全体の約６０％を占めているといわれている。物理的な障害や進行性の角膜内皮ジストロフィー（代表的には、フックス角膜内皮変性症（Fuchs corneal dystrophy））などにより、角膜内皮に欠損が生じると、不可逆的な角膜浮腫が生じた水疱性角膜症（bullous keratopathy）になる。視力低下が著しい場合には、角膜移植が必要となる。
ヒトの角膜内皮細胞は生体内では細胞***しないが、インビトロ（In vitro）での培養が検討されてきている（非特許文献１及び２参照）。インビトロ（In vitro）で培養して増殖させたヒトの角膜内皮細胞を角膜に移植して治療することが可能となるからである。
このようなことから、角膜内皮細胞の接着性を促進させ、また、角膜内皮の損傷部位を修復するためや、角膜内皮の機能の維持や回復のための薬剤だけでなく、ヒトの角膜内皮細胞を培養増殖させるための培養液や、移植までの角膜内皮細胞や角膜内皮組織を保存するための保存液、更には角膜厚を調節する薬剤などの開発が望まれている。Corneal endothelium dysfunction is said to account for about 60% of all corneal dysfunction. Bullous cornea with irreversible corneal edema when the corneal endothelium is deficient due to a physical disorder or progressive corneal endothelial dystrophy (typically Fuchs corneal dystrophy) Becomes bullous keratopathy. If visual loss is significant, corneal transplantation is required.
Human corneal endothelial cells do not divide in vivo, but in vitro culture has been studied (see Non-Patent Documents 1 and 2). This is because human corneal endothelial cells cultured and proliferated in vitro can be transplanted into the cornea for treatment.
Because of this, it promotes adhesion of corneal endothelial cells, repairs damaged areas of corneal endothelium, and maintains and restores corneal endothelium function, as well as human corneal endothelial cells. The development of a culture solution for cultivating corneal cells, a preservation solution for preserving corneal endothelial cells and corneal endothelial tissues until transplantation, and a drug for regulating corneal thickness is desired.
Ｒｈｏキナーゼ（Rho-associated, coiled-coil containing protein kinase : ROCK）は、分子量約１６０ｋＤａのセリンスレオニンリン酸化酵素であり、その遺伝子は線虫やショウジョウバエなどの下等動物からヒトなどまで広く保存されている。Ｒｈｏキナーゼは平滑筋細胞の収縮だけでなく、細胞の形態制御や、遊走や、遺伝子発現の制御などの生理機能に関与しており、Ｒｈｏキナーゼ阻害剤は循環器疾患などの治療薬として開発が進められている。
また、近年では、緑内障の治療などの眼疾患のための局所投与薬としても開発されてきている。さらに、角膜内皮細胞の培養についても、Ｒｈｏキナーゼ阻害剤の１種である（＋）−トランス−４−（１−アミノエチル）−１−（４−ピリジルアミノカルボニル）シクロヘキサン（以下、Ｙ−２７６３２という）の存在下でウサギの角膜内皮細胞を培養できることが報告され（非特許文献３及び４参照）、サルの角膜内皮細胞も同様に培養できることが報告されている（特許文献１参照）。特許文献１では、１−（５−イソキノリンスルホニル）−１，４−ホモピペラジン（以下、ファスジルという）でもウサギの角膜内皮細胞の接着性を促進することが報告されている。そして、ウサギの角膜内皮損傷についてのＹ−２７６３２による処置（非特許文献５参照）や、ヒトのフックス角膜内皮変性症におけるＹ−２７６３２による治療（非特許文献６参照）が報告されてきている。また、ウサギの角膜内皮損傷についての（Ｒ）−（＋）−Ｎ−（１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル）−４−（１−アミノエチル）ベンズアミド（以下、Ｙ−３９９８３という）による処置（特許文献２及び非特許文献７参照）も報告されている。非特許文献７によれば、Ｙ−３９９８３とＹ−２７６３２のＲｈｏキナーゼに対する５０％阻止濃度（ＩＣ５０）は、それぞれ０．００３６μＭと０．１１μＭであり、約３０倍の相違があり、この違いが角膜内皮細胞に対する活性の相違となったのではないかとされている。
これらの文献で使用されているＹ−２７６３２とＹ−３９９８３は、いずれもＮ−ピリジルアミド系の化合物であるが、ファスジルは１−スルホン−１，４−ホモピペラジン系の化合物である。Rho-associated (coiled-coil containing protein kinase: ROCK) is a serine threonine kinase with a molecular weight of about 160 kDa, and its gene is widely conserved from lower animals such as nematodes and Drosophila to humans. Yes. Rho kinase is involved not only in the contraction of smooth muscle cells, but also in physiological functions such as cell morphology control, migration, and gene expression control. Rho kinase inhibitors are being developed as therapeutic agents for cardiovascular diseases and the like. It is being advanced.
In recent years, it has also been developed as a locally administered drug for eye diseases such as the treatment of glaucoma. Furthermore, also for the culture of corneal endothelial cells, (+)-trans-4- (1-aminoethyl) -1- (4-pyridylaminocarbonyl) cyclohexane (hereinafter referred to as Y-27632), which is one of Rho kinase inhibitors. It is reported that rabbit corneal endothelial cells can be cultured in the presence of (see Non-Patent Documents 3 and 4), and monkey corneal endothelial cells can also be cultured in the same manner (see Patent Document 1). In Patent Document 1, it is reported that 1- (5-isoquinolinesulfonyl) -1,4-homopiperazine (hereinafter referred to as fasudil) also promotes adhesion of rabbit corneal endothelial cells. And the treatment by Y-27632 (refer nonpatent literature 5) about the corneal-endothelial damage of a rabbit and the treatment by Y-27632 (refer nonpatent literature 6) in the human Fuchs corneal-endothelial degeneration have been reported. In addition, (R)-(+)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide (hereinafter Y) -39983) (see
Y-27632 and Y-39983 used in these documents are both N-pyridylamide compounds, but fasudil is a 1-sulfone-1,4-homopiperazine compound.
一方、１−（４−フルオロ−５−イソキノリンスルホニル）−２−メチル−１，４−ホモピペラジン（以下、化合物Ａということがある）は、ファスジルと同様に１−スルホン−１，４−ホモピペラジン系の化合物であり、ファスジルに比べて選択性が有り、Ｒｈｏキナーゼ阻害活性もファスジルよりも強いことが記載され、喘息の予防・治療に有用であることが報告されている（特許文献３の化合物６参照）。特許文献３には、化合物ＡとファスジルとのＲｈｏキナーゼに対する５０％阻止濃度（ＩＣ５０）は、それぞれ０．２μＭと１．５μＭであるとされている。前記の非特許文献７の記載と比べると、化合物ＡのＲｈｏキナーゼに対する５０％阻止濃度（ＩＣ５０）は、ファスジルよりは強いが、Ｙ−２７６３２よりは弱いか同程度であると考えられる。
化合物Ａを用いた眼疾患については、化合物Ａと炭酸脱水酵素阻害剤とを組み合わせることにより緑内障の予防・治療に有用であること（特許文献４参照）や、化合物Ａが眼底疾患の予防・治療に有用であること（特許文献５参照）が報告されているが、化合物Ａによる角膜厚に対する作用は報告されていない。On the other hand, 1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine (hereinafter sometimes referred to as Compound A) is similar to 1-sulfone-1,4-homo, similar to fasudil. It is a piperazine-based compound, has selectivity compared to fasudil, and has a strong Rho kinase inhibitory activity than fasudil, and is reported to be useful for the prevention and treatment of asthma (Patent Document 3). Compound 6). Patent Document 3 states that the 50% inhibitory concentration (IC 50 ) for Rho kinase of Compound A and Fasudil is 0.2 μM and 1.5 μM, respectively. Compared to the description in Non-Patent Document 7, the 50% inhibitory concentration (IC 50 ) for Rho kinase of Compound A is stronger than Fasudil, but is considered to be weaker or comparable to Y-27632.
Regarding eye diseases using Compound A, it is useful for the prevention and treatment of glaucoma by combining Compound A and a carbonic anhydrase inhibitor (see Patent Document 4), and the prevention and treatment of fundus disease for Compound A. However, the effect of Compound A on the corneal thickness has not been reported.
本発明は、角膜厚の維持や回復のための角膜厚調節剤、及びこれを用いた角膜厚の維持や回復のための手段、例えば角膜菲薄化の手段を提供する。 The present invention provides a corneal thickness regulator for maintaining and recovering corneal thickness, and means for maintaining and recovering corneal thickness using the same, for example, means for thinning the cornea.
本発明者らは、上記課題を解決すべく鋭意研究を重ねた結果、１−（４−フルオロ−５−イソキノリンスルホニル）−２−メチル−１，４−ホモピペラジン（以下、化合物Ａと表記することがある。）若しくはその塩又はそれらの溶媒和物が、角膜の厚さを薄く維持することができ、角膜組織に対してより安全で有効性に優れた薬剤となることを見出した。また、点眼投与することも可能であり、患者の負担の少ない製剤化も可能であることを見出した。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have found 1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine (hereinafter referred to as Compound A). It has been found that a corneal thickness can be kept thin, and that the salt or solvate thereof is a safer and more effective drug for corneal tissue. It was also found that it can be administered by eye drops and can be formulated with less burden on the patient.
即ち、本発明は、１−（４−フルオロ−５−イソキノリンスルホニル）−２−メチル−１，４−ホモピペラジン若しくはその塩又はそれらの溶媒和物を含有してなる角膜厚調節剤に関する。
また、本発明は、１−（４−フルオロ−５−イソキノリンスルホニル）−２−メチル−１，４−ホモピペラジン若しくはその塩又はそれらの溶媒和物を含有してなる角膜菲薄化剤に関する。
さらに、本発明は、１−（４−フルオロ−５−イソキノリンスルホニル）−２−メチル−１，４−ホモピペラジン若しくはその塩又はそれらの溶媒和物を含有してなる角膜浮腫の予防剤に関する。That is, the present invention relates to a corneal thickness regulator comprising 1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof.
The present invention also relates to a corneal thinning agent comprising 1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof.
Furthermore, the present invention relates to a preventive agent for corneal edema comprising 1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof.
本発明をより詳細に説明すれば、以下のとおりである。
（１）１−（４−フルオロ−５−イソキノリンスルホニル）−２−メチル−１，４−ホモピペラジン若しくはその塩又はそれらの溶媒和物を含有してなる角膜厚調節剤。
（２）１−（４−フルオロ−５−イソキノリンスルホニル）−２−メチル−１，４−ホモピペラジンが、（Ｓ）−（−）−１−（４−フルオロ−５−イソキノリンスルホニル）−２−メチル−１，４−ホモピペラジン（以下、化合物Ｂと表記することがある。）である、前記（１）に記載の角膜厚調節剤。
（３）角膜厚調節剤が、角膜菲薄化剤である、前記（１）又は（２）に記載の角膜厚調節剤。
（４）角膜厚調節剤が、角膜浮腫の予防及び／又は治療剤である、前記（１）又は（２）に記載の角膜厚調節剤。
（５）角膜厚調節剤が、角膜内皮障害の予防及び／又は治療剤である、前記（１）又は（２）に記載の角膜厚調節剤。
（６）角膜内皮障害が、水疱性角膜症又は角膜内皮炎などの角膜内皮疾患である、前記（５）に記載の角膜厚調節剤。
（７）角膜厚調節剤が、液剤である、前記（１）から（６）のいずれか１項に記載の角膜厚調節剤。
（８）角膜厚調節剤が、点眼剤である、前記（１）から（７）のいずれか１項に記載の角膜厚調節剤。
（９）角膜が、霊長類の角膜である、前記（１）から（８）のいずれか１項に記載の角膜厚調節剤。
（１０）角膜が、ヒトの角膜である、前記（１）から（９）のいずれか１項に記載の角膜厚調節剤。
（１１）１−（４−フルオロ−５−イソキノリンスルホニル）−２−メチル−１，４−ホモピペラジン若しくはその塩又はそれらの溶媒和物、及び製薬上許容される担体を混合する工程を含有してなる、前記（１）から（１０）のいずれか１項に記載の角膜厚調節剤の製剤を製造する方法。The present invention will be described in detail as follows.
(1) A corneal thickness regulator comprising 1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof.
(2) 1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine is (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2 The corneal thickness regulator according to (1), which is methyl-1,4-homopiperazine (hereinafter sometimes referred to as compound B).
(3) The corneal thickness adjusting agent according to (1) or (2), wherein the corneal thickness adjusting agent is a corneal thinning agent.
(4) The corneal thickness adjusting agent according to (1) or (2), wherein the corneal thickness adjusting agent is a preventive and / or therapeutic agent for corneal edema.
(5) The corneal thickness regulator according to (1) or (2), wherein the corneal thickness regulator is a preventive and / or therapeutic agent for corneal endothelial injury.
(6) The corneal endothelial dysfunction according to (5), wherein the corneal endothelial disorder is a corneal endothelial disease such as bullous keratopathy or corneal endotheliitis.
(7) The corneal thickness adjusting agent according to any one of (1) to (6), wherein the corneal thickness adjusting agent is a liquid agent.
(8) The corneal thickness adjusting agent according to any one of (1) to (7), wherein the corneal thickness adjusting agent is an eye drop.
(9) The corneal thickness regulator according to any one of (1) to (8), wherein the cornea is a primate cornea.
(10) The corneal thickness regulator according to any one of (1) to (9), wherein the cornea is a human cornea.
(11) A step of mixing 1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof and a pharmaceutically acceptable carrier. A method for producing a preparation of a corneal thickness regulator according to any one of (1) to (10).
本発明は、角膜厚変調をきたしている角膜障害を、予防及び／又は治療するための角膜厚調節剤を提供するものである。本発明の角膜厚調節剤は、水疱性角膜症、角膜内皮炎等の角膜内皮疾患や、角膜移植等による角膜内皮異常などの各種の角膜内皮障害を予防及び／又は治療することができる。そして、本発明の角膜厚調節剤は、有効成分が低濃度でも有効であり、角膜の厚さを薄く維持することができ副作用の少ない安全で有効性の高い医薬組成物として使用することができる。
また、本発明の角膜厚調節剤は、患者の負担が少ない点眼剤として提供することができる。The present invention provides a corneal thickness adjusting agent for preventing and / or treating a corneal disorder causing corneal thickness modulation. The corneal thickness regulator of the present invention can prevent and / or treat various corneal endothelial disorders such as corneal endothelial diseases such as bullous keratopathy and corneal endotheliitis, and corneal endothelial abnormalities due to corneal transplantation and the like. The corneal thickness regulator of the present invention is effective even at a low concentration of the active ingredient, can maintain the corneal thickness thin, and can be used as a safe and highly effective pharmaceutical composition with few side effects. .
Moreover, the corneal thickness regulator of the present invention can be provided as an eye drop with less burden on the patient.
以下に本発明をより詳細に説明する。
本発明における化合物Ａは、１個の不斉炭素原子を有しており、（Ｒ）体と（Ｓ）体が存在している。本発明においては、（Ｒ）体若しくは（Ｓ）体、又はこれらの混合物のいずれかを用いることができる。医薬の有効成分としては、（Ｒ）体又は（Ｓ）体の高純度の光学活性体が好ましい。（Ｒ）体と（Ｓ）体の中では活性の点から、（Ｓ）体が好ましい。本明細書においては、（Ｓ）体を単に化合物Ｂと表記する。Hereinafter, the present invention will be described in more detail.
Compound A in the present invention has one asymmetric carbon atom, and (R) isomer and (S) isomer exist. In the present invention, either the (R) isomer, the (S) isomer, or a mixture thereof can be used. As an active ingredient of a medicine, (R) -form or (S) -form high-purity optically active form is preferable. Among the (R) and (S) isomers, the (S) isomer is preferred from the viewpoint of activity. In this specification, the (S) form is simply referred to as Compound B.
本発明の有効成分である１−（４−フルオロ−５−イソキノリンスルホニル）−２−メチル−１，４−ホモピペラジンは、脳血管治療剤や喘息治療剤、サブスタンスＰ拮抗作用、ロイコトリエンＤ４拮抗作用及びＲｈｏキナーゼ阻害作用を有する化合物として公知（特許文献３参照）であり、公知の方法、例えば、国際特許公開第９９／２０６２０号パンフレットに記載の方法により製造することができる。1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine, which is an active ingredient of the present invention, is a cerebrovascular therapeutic agent, asthma therapeutic agent, substance P antagonism, leukotriene D 4 antagonism. It is known as a compound having an action and a Rho kinase inhibitory action (see Patent Document 3), and can be produced by a known method, for example, a method described in International Patent Publication No. 99/20620 pamphlet.
化合物Ａの塩としては、例えば塩酸、硫酸、硝酸、フッ化水素酸、臭化水素酸等の無機酸の塩、又は酢酸、酒石酸、乳酸、クエン酸、フマル酸、マレイン酸、コハク酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、トルエンスルホン酸、ナフタレンスルホン酸、カンファースルホン酸等の有機酸との塩が挙げられ、特に塩酸塩が好ましい。
化合物Ａ又はその塩は、未溶媒和型のみならず水和物又は溶媒和物としても存在することができる。水和物が好ましいが、本発明においては、全ての結晶型及び水和若しくは溶媒和物を含むものである。Examples of the salt of Compound A include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrofluoric acid, hydrobromic acid, or acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methane Examples include salts with organic acids such as sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid and camphorsulfonic acid, and hydrochloride is particularly preferable.
Compound A or a salt thereof can exist not only as an unsolvated form but also as a hydrate or a solvate. Hydrates are preferred, but in the present invention, all crystal forms and hydrates or solvates are included.
本発明において、「角膜厚調節剤」とは、角膜の厚さを調整して、正常な角膜の機能を維持させるものである。角膜の厚さは主として角膜内皮の機能に依存しており、本発明の「角膜厚調節剤」は、角膜内皮機能の亢進又は低下などの角膜内皮に機能障害が生じている場合に、当該機能を調節して、より正常な状態とすることにより、角膜の厚さを調整することができると考えられる。即ち、角膜内皮は、ポンプ機能やバリア機能などの視力維持のための重要な機能を有しており、これらの機能が亢進した場合には、これを抑制し、またこれらの機能が低下している場合には、これを促進することにより、角膜厚をより正常にするものであると考えられる。
本発明の「角膜厚調節剤」を投与することにより、角膜内皮の機能を調整して、角膜の厚さを薄くする（菲薄化）ことができるので、本発明の「角膜厚調節剤」は、角膜菲薄化剤、角膜浮腫の予防・治療剤、及び/又は角膜内皮障害の予防・治療剤としても使用することができる。In the present invention, the “corneal thickness adjusting agent” adjusts the thickness of the cornea to maintain the normal function of the cornea. The thickness of the cornea depends mainly on the function of the corneal endothelium, and the “corneal thickness regulator” of the present invention is capable of functioning when a dysfunction occurs in the corneal endothelium, such as an increase or decrease in corneal endothelial function. It is considered that the thickness of the cornea can be adjusted by adjusting to a more normal state. That is, the corneal endothelium has important functions for maintaining visual acuity such as a pump function and a barrier function, and when these functions are enhanced, it is suppressed and these functions are reduced. It is considered that the corneal thickness becomes more normal by promoting this.
By administering the “corneal thickness regulator” of the present invention, the function of the corneal endothelium can be adjusted to reduce the thickness of the cornea (thinning). , A corneal thinning agent, a preventive / therapeutic agent for corneal edema, and / or a prophylactic / therapeutic agent for corneal endothelial dysfunction.
本発明の「角膜厚調節剤」は、当該分野で汎用されている通常の製剤化技術により、眼局所投与に適した剤型に製剤化される。剤型としては、例えば、前房内注射液、眼灌流液、又は点眼液等の液剤が好ましいが、これに限定されるものではない。好ましい製剤としては、前房内注射液や眼灌流液は治療効果の点から好ましい剤型ではあるが患者の負担も大きく、投与の容易さから点眼剤が挙げられる。
本発明の点眼薬は、本発明の有効成分である化合物Ａ、好ましくは化合物Ｂ若しくはその塩又はそれらの溶媒和物、及び点眼薬に許容される担体を含有するものである。The “corneal thickness regulator” of the present invention is formulated into a dosage form suitable for topical ocular administration by a conventional formulation technique widely used in the art. As the dosage form, for example, a liquid agent such as an injection solution in the anterior chamber, an eye perfusate, or an eye drop is preferable, but it is not limited thereto. Preferable preparations include an anterior chamber injection solution and ocular perfusate which are preferable dosage forms from the viewpoint of therapeutic effect, but they impose a heavy burden on patients and include eye drops for ease of administration.
The eye drop of the present invention contains Compound A, preferably Compound B or a salt thereof or a solvate thereof, which is an active ingredient of the present invention, and a carrier acceptable for eye drops.
点眼剤を調製する場合、例えば、所望な上記成分を滅菌精製水、生理食塩水等の水性溶剤、又は綿実油、大豆油、ゴマ油、落花生油等の植物油等の非水性溶剤に溶解又は懸濁させ、所定の浸透圧に調整し、濾過滅菌等の滅菌処理を施すことにより行うことができる。なお、眼軟膏剤を調製する場合は、前記各種の成分の他に、軟膏基剤を含むことができる。前記軟膏基剤としては、特に限定されないが、ワセリン、流動パラフィン、ポリエチレン等の油性基剤； 油相と水相とを界面活性剤等により乳化させた乳剤性基剤； ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、ポリエチレングリコール等からなる水溶性基剤等が好ましく挙げられる。 When preparing eye drops, for example, the desired components described above are dissolved or suspended in an aqueous solvent such as sterile purified water or physiological saline, or a non-aqueous solvent such as vegetable oil such as cottonseed oil, soybean oil, sesame oil, or peanut oil. The osmotic pressure can be adjusted to a predetermined osmotic pressure and subjected to sterilization such as filtration sterilization. In addition, when preparing an eye ointment, an ointment base can be included in addition to the various components described above. The ointment base is not particularly limited, but is an oily base such as petrolatum, liquid paraffin, or polyethylene; an emulsion base in which an oil phase and an aqueous phase are emulsified with a surfactant or the like; hydroxypropylmethylcellulose, carboxymethylcellulose A water-soluble base composed of polyethylene glycol or the like is preferred.
化合物Ａ、好ましくは化合物Ｂ若しくはその塩又はそれらの溶媒和物を本発明の「角膜厚調節剤」に用いる場合、その投与量は、患者の体重、年齢、性別、症状、投与形態及び投与回数等によって異なるが、通常は成人に対して、化合物Ａ、好ましくは化合物Ｂとして、１日０．０２５〜１００００μｇ、好ましくは０．０２５〜２０００μｇ、より好ましくは０．１〜２０００μｇ、さらに０．０２５〜２００μｇ、０．０２５〜１００μｇの範囲が挙げられる。
点眼剤として使用する場合には、有効成分を約０．０００１〜５ｗ／ｖ％、好ましくは約０．０１〜４ｗ／ｖ％の濃度で使用することができる。When Compound A, preferably Compound B or a salt thereof, or a solvate thereof is used in the “corneal thickness regulator” of the present invention, the dosage is the patient's body weight, age, sex, symptom, dosage form and administration frequency. Although it varies depending on the like, it is usually 0.025 to 10,000 μg, preferably 0.025 to 2000 μg, more preferably 0.1 to 2000 μg, more preferably 0.025 per day as Compound A, preferably Compound B, for adults. The range of -200 microgram and 0.025-100 microgram is mentioned.
When used as an eye drop, the active ingredient can be used at a concentration of about 0.0001 to 5 w / v%, preferably about 0.01 to 4 w / v%.
また、投与回数は、特に限定されないが、１回又は数回に分けて投与するのが好ましく、液体点眼剤の場合は、１回に１〜数滴点眼すればよい。 The number of administrations is not particularly limited, but it is preferable to administer once or several times. In the case of liquid eye drops, one to several drops may be instilled at a time.
本発明の「角膜厚調節剤」の投与対象としては、哺乳動物（例えば、ヒト、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ウマ、ヒツジ、サル等）が挙げられる。好ましい哺乳動物としてはヒト、サルなどの霊長類が挙げられる。特に好ましくはヒトが挙げられる。 Examples of the administration target of the “corneal thickness regulator” of the present invention include mammals (eg, human, mouse, rat, hamster, rabbit, cat, dog, cow, horse, sheep, monkey, etc.). Preferred mammals include primates such as humans and monkeys. Particularly preferred is human.
ヒトにおける角膜の厚さの変化：
眼科疾患を有する対象における化合物Ｂの長期投与試験において、角膜に対する影響を調べた（２７−３４例）。すなわち、化合物Ｂ０．４％点眼液の１日２回投与、５２週点眼群において、投与開始前（０週）、投与２週後、投与４週後、以降は４週毎に、角膜厚をパキメーターにて測定した。測定は５回行い、５回の平均値を採用した。測定日は９時に点眼し、１１時に測定した。なお、２８週後、５２週後、フォローアップ（最終投与日から７−２８日後）時は、９時（２８週後、５２週後においては点眼前）と１１時の２回測定した。Changes in corneal thickness in humans:
In a long-term administration test of Compound B in subjects with ophthalmic diseases, the effect on the cornea was examined (27-34 cases). That is, Compound B 0.4% ophthalmic solution administered twice a day, in the 52-week ophthalmic group, before the start of administration (week 0), after 2 weeks of administration, after 4 weeks of administration, and thereafter every 4 weeks, It was measured with a pachymeter. The measurement was performed 5 times and the average value of 5 times was adopted. The measurement day was instilled at 9 o'clock and measured at 11 o'clock. In addition, after 28 weeks, 52 weeks, and follow-up (7-28 days after the last administration day), the measurement was performed twice at 9 o'clock (after 28 weeks and before instillation after 52 weeks) and 11:00.
結果を図１に示す。図１上は右眼の結果であり、図１下は左眼の結果である。縦軸は０週からの変化値（μm）であり、横軸は投与週を示す。２８週、５２週、フォローアップ（f/u）では、９時測定を（０）で、１１時測定を（２）として示した。なお、投与開始前（０週）における角膜厚は右眼が５３１．６±２８．０μｍ、左眼が５３０．９±２７．９μｍ（いずれも平均値±標準偏差）であった。
The results are shown in FIG. FIG. 1 shows the result for the right eye, and FIG. 1 shows the result for the left eye. The vertical axis represents the change value (μm) from
本発明の化合物Ｂの投与期間中は角膜の厚さが減少することが分かる。投与を継続しても、角膜の厚さはほぼ一定値に維持される。また、２８週後、及び５２週後では、点眼前（０）では角膜の厚さが化合物Ｂの投与開始前（０週）の値に戻る傾向であったが、点眼２時間後（２）には角膜の厚さは減少していた。 It can be seen that the cornea thickness decreases during the administration period of Compound B of the present invention. Even if administration is continued, the thickness of the cornea is maintained at a substantially constant value. Further, after 28 weeks and 52 weeks, the cornea thickness tended to return to the value before the start of administration of Compound B (0 week) before instillation (0), but 2 hours after instillation (2) The cornea thickness was decreased.
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